Metal- and Base-Free Room-Temperature Amination of Organoboronic Acids with N-Alkyl Hydroxylamines

Article abstract of DOI:10.1002/anie.201802782

We have found that readily available N-alkyl hydroxylamines are effective reagents for the amination of organoboronic acids in the presence of trichloroacetonitrile. This amination reaction proceeds rapidly at room temperature and in the absence of added metal or base, it tolerates a remarkable range of functional groups, and it can be used in the late-stage assembly of two complex units.

Full text of DOI:10.1002/anie.201802782

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201802782
German Edition: DOI: 10.1002/ange.201802782
Hydroxylamines
Metal- and Base-Free Room-Temperature Amination of
Organoboronic Acids with N-Alkyl Hydroxylamines
Hong-Bao Sun+, Liang Gong+, Yu-Biao Tian, Jin-Gui Wu, Xia Zhang, Jie Liu, Zhengyan Fu,
and Dawen Niu*
Abstract: We have found that readily available N-alkyl
hydroxylamines are effective reagents for the amination of
organoboronic acids in the presence of trichloroacetonitrile.
This amination reaction proceeds rapidly at room temperature
and in the absence of added metal or base, it tolerates
a remarkable range of functional groups, and it can be used
in the late-stage assembly of two complex units.
A
s amines are ubiquitous in pharmaceuticals, agrochemicals,
functional materials, and natural products,[1] methods for
ꢀ
making C N bonds are highly important in chemistry. For
ꢀ
example, the advent of transition-metal-catalyzed C N cross-
coupling reactions[2] has largely addressed the difficulty of
ꢀ
building Caryl N bonds, and profoundly influenced many
fields such as medicinal chemistry, materials science, and
chemical biology. However, in addition to the required basic
reaction conditions, one drawback of these methods is the use
of transition metals (TMs), whose removal, if required, can be
cumbersome and expensive. TM-free methods for making
ꢀ
Caryl N bonds are frequently needed in various disciplines,
and actively pursued by the synthetic community, but have
remained underdeveloped.[3]
Scheme 1. Methods for the conversion of boronic acids into (aryl)
Organoboronic acid derivatives (BAs) are a fundamental
class of intermediates in synthesis because of their synthetic
versatility and their compatibility with many functional
groups.[4] Moreover, BAs are readily available from commer-
cial sources and can be prepared by a large and increasing
number of synthetic methods.[5] Recently, tremendous efforts
have been devoted to the conversion of BAs into amines.
Classic examples include the Chan–Lam–Evans reaction,[6] in
which BAs undergo oxidative couplings with amines to give
anilines (Scheme 1a, 1 + 2!4). Additionally, the groups of
Lei, Liebeskind, Lalic, and others have reported on the
amination of BAs with N-chloro amides or N-alkyl hydroxyl-
amine derivatives in the presence of copper- or rhodium-
based catalysts (Scheme 1a, 1 + 3!4).[7] Notably, reactions
amines.
converting BAs into amines are unconventional in that the
ꢀ
C atom in the resulting C N bond could be viewed as
a nucleophile.[8] With recent developments, methods in this
category have become important alternatives to produce
amines. However, the aforementioned reactions also require
the participation of transition metals.
TM-free methods for the conversion of BAs into amines
under mild conditions would be of importance in chemistry
(Scheme 1b, 5 + 6!7). Whereas TM-free amination reac-
tions of the more Lewis acidic organoboron reagents, such as
dihaloboranes, dialkyl borinates, and trialkyl boranes, by
electrophilic nitrogen sources are known,[9,10] aminations of
BAs are less common[3a,b] and usually require harsh reaction
conditions. For instance, N,N-dialkyl O-benzoyl hydroxyl-
amines and organic azides have been used to aminate aryl
boroxines and aryl boronic acids, respectively, but only at high
temperatures (> 1308C).[11] Lithiated methoxyamine is an
effective amination reagent for aryl and alkyl pinacol
boronates.[12] However, the high basicity of this reagent
limits the variety of compatible functional groups. The
groups of Kꢀrti and Falck reported the elegant use of
O-(2,4-dinitrophenyl)hydroxylamine as an aminating agent
for aryl boronic acids under mild conditions.[13] Nevertheless,
as pointed out by the authors, aryl boronic acids containing
[*] H.-B. Sun,[+] L. Gong,[+] Y.-B. Tian, J.-G. Wu, X. Zhang, J. Liu, Z. Fu,
Prof. D. Niu
State Key Laboratory of Biotherapy and Cancer Center
West China Hospital
and
School of Chemical Engineering, Sichuan University
No. 17 Renmin Nan Road, Chengdu, 610041 (China)
E-mail: niudawen@scu.edu.cn
Homepage: http://www.theniugroup.com
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201802782.
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Table 1: Amination of organoboronic acids: Proposed strategy and
N-acyl or carbonyl groups, or those with unprotected N atoms
(e.g., indoles) or S atoms, are not suitable substrates. More-
over, this reaction gives primary anilines as the products, and
thus cannot be used to build up molecular complexity. Most
recently, the conversion of BAs into diaryl amines was
reported.[3b]
optimization of the reaction conditions.[a]
In continuation of our interest in developing novel
methods for the synthesis of amines,[14] we herein report
a mild transformation (Scheme 1c, 8 + 11!12) that converts
BAs into secondary amines at ambient temperature (288C)
and in the absence of added metal or base. Our method
employs readily available N-alkyl hydroxylamines 11 as the
electrophilic nitrogen source. Remarkably, while the parent
hydroxylamine (9) has been used as an oxygen-transfer agent
that converts aryl boronic acid derivatives into phenols (8 +
9!10),[15] we establish in this work that N-alkyl hydroxyl-
amine 11 is an effective reagent for the amination of BAs (8)
in the presence of a stoichiometric amount of trichloroace-
tonitrile (CCl3CN). This process was adopted for the amina-
tion of both aryl and alkyl boronic acids. Moreover, the
amination of alkyl boronic acids was found to be stereo-
retentive. This method tolerates a remarkable range of
functional groups, including amides, ketones, esters, unpro-
tected alcohols, and carboxylic acids. The reaction is opera-
tionally simple, and can be performed open to air. The
generality of this method was demonstrated by its application
in the preparation of products containing peptide side chains
or carbohydrate motifs.
Entry
Activating agent
Solvent
T
[8C]
Yield[a]
[%]
1
2
3
4
5
6
7
8
9
Ac2O, Et3N
MsCl, Et3N
Tf2O, Et3N
Py·SO3
CCl3CN
CCl3CN
CCl3CN
CCl3CN
CCl3CN
CCl3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH3CN
THF
iPrOH
tBuOH
tBuOH
tBuOH
25–80
25–80
25–80
25–80
28
28
28
28
28
<5
<5
<5
<5
71
70
40
48
<5
99
10
11[c]
12[d]
28
28
28
CCl3CN
CCl3CN
99
92[b]
[a] Unless otherwise noted, all reactions were performed on 0.2 mmol
scale. The yields were determined by H NMR analysis with 1,3,5-
trimethylbenzene as the internal standard. [b] Yield of isolated product.
[c] Reaction mixture open to air. [d] With 7 mmol of 16, 20 min.
1
Our proposed strategy to achieve the amination of BAs is
outlined in Table 1a (13 + 11!12 via 14/15). We wondered
whether N-alkyl hydroxylamines could be turned into an
effective aminating reagent to deliver an N-alkyl group.
Given the ready availability of both reaction partners, if
successful, this method might well be applicable in the late-
solvents, such as iPrOH (entry 9), led to no observable
product, highlighting the significant impact of solvent on the
reaction outcome. Importantly, we found that this reaction
could be performed open to air (entry 11). Lastly, this
reaction was run on 7 mmol scale, yielding 1.18 g of 18 in
92% yield within 20 min (entry 12). Among all boronic acid
derivatives tested, we found that 2,4,6-triphenylboroxine gave
similar results to 16, while others, such as phenylboronic acid
pinacol ester (PhBpin) or potassium phenyltrifluoroborate
(PhBF3K), were unreactive (results not shown).
We next explored the substrate scope of this transforma-
tion (Figure 1). The reaction displays significant scope with
respect to the organoboronic acid partner (Figure 1a). Both
electron-rich (19k–19m, 19r–19s) and electron-deficient
(19e, 19n–19q) aryl groups were tolerated. Substitution at
the ortho (19 f–9h), meta (19i, 9j), or para position (19a–19e)
was possible. Not surprisingly, aryl halides were stable under
the reaction conditions (19a–19d), providing opportunities
for further derivatization. Various functional groups, includ-
ing ketone (19n), ester (19m, 19mq), nitro (19o), free
carboxylic acid (19p), free phenol (19r), and free indole
(19x) moieties, were all tolerated. Aryl boronic acids bearing
fused (19t) and heterocyclic ring systems (19u–19aa) reacted
smoothly in this reaction. Furthermore, a boronic acid derived
from estrone was efficiently aminated (19ab). It is important
to note that the amination of alkyl boronic acids/esters seems
more challenging.[12] Nevertheless, we found that our method
could be employed for the amination of alkyl boronic acids as
ꢀ
stage coupling of complex units through C N bond forma-
tion. N-Alkyl hydroxylamines are compatible with BAs,
which we attributed to the poor leaving group ability of the
free hydroxy group (cf. 11 or 14). We surmised that we could
facilitate the B-to-N migration of the R1 group in 14 through
ꢀ
activating the N O bond by installing a leaving group on the
O atom in situ (cf. 15). This in situ activation strategy would
obviate the need for isolating potentially unstable intermedi-
ates, permit a rapid screen of various activation conditions,
and enhance the chance of identifying an efficient trans-
formation.
Guided by this plan, we investigated the model reaction
between phenylboronic acid (16) and N-benzyl hydroxyl-
amine (17), as shown in Table 1b. After mixing 16 and 17 in
CH2Cl2, we tested various conditions that would likely
activate the O atom in 17. Conventional reagents such as
Ac2O, MsCl, or Tf2O gave no observable product (entries 1–
3). The use of Py·SO3 did not effect this transformation either
(entry 4). Our initial success resulted from the use of
CCl3CN:[16] In the absence of any additional base and at
ambient temperature, the desired N-benzyl aniline was
produced in 71% yield (entry 5). A further screen of reaction
conditions (entries 6–10) revealed tBuOH to be the optimal
solvent, in which 18 was formed in near-quantitative yield
(entry 10). In sharp contrast, the use of other alcoholic
2
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Figure 2. Synthetic applications. Unless otherwise noted, the reactions
were performed on 0.15 mol scale. See the Supporting Information for
details.
method are key to the success of the above-mentioned
reactions. Given these attractive features, we anticipate that
this method might be adopted in other complex settings,
including in the construction of chemical libraries.
We then carried out various experiments to gain mech-
anistic insight into this reaction (Scheme 2). N-Alkyl hydrox-
Figure 1. Substrate scope. Reaction conditions: Boronic acid
(0.3 mmol), hydroxylamine (0.45 mmol), and CCl3CN (0.45 mmol) in
tBuOH (0.5 ml) at 288C for 1–8 h. Yields of isolated products are
1
given. For 19p and 19x, the yields were determined by H NMR
analysis with 1,3,5-trimethylbenzene as the internal standard. For 20a–
20 f, the boronic acids were used in excess (2.0–3.0 equiv). Products
20a–20 f were isolated as the corresponding tosyl amides. Yields of
isolated products are given. See the Supporting Information for
details.
Scheme 2. Mechanistic studies.
well (20a–20 f). Our process is unique in that it proceeds
under almost neutral conditions.
Hydroxylamines with various functional groups partici-
pate in this reaction as well (Figure 1b). For instance, those
with aryl rings of different electronic properties (21a–21e)
and with heteroaryl substituents (21 f–21h) are suitable
substrates. Functional groups including aryl halides (21a),
alkenes (21j), and esters (21k) were accommodated, too. The
hydroxylamines derived from lysine (21k), glucose (21l), and
the natural product dehydroabietylamine (21m) can all be
employed as efficient aminating agents in this reaction. The
use of N-cycloheptyl hydroxylamine gave the corresponding
amine 21n, albeit in modest yield.
To further show the utility of this method, we conducted
the reactions shown in Figure 2. An aryl boronic acid
embedded in a tripeptide backbone was aminated in high
yield (22!23). In addition, this method was successfully used
to unite a dehydroabietylamine scaffold with a steroidal
moiety under metal- and base-free conditions (24). Lastly, we
also applied this method in the coupling of hydroxylamines
with carbohydrate backbones with an amino acid derivative
(25) and with a tripeptide (26). The broad substrate scope,
tolerance of air and moisture, and operational ease of this
ylamines react with trichloroacetonitrile to give the corre-
sponding O-imino hydroxylamines.[16] We monitored the
reaction of 27 and trichloroacetonitrile in tBuOH by
19F NMR spectroscopy, and found that 28 was formed in
almost quantitative yield within 1 min (Scheme 2a). More-
over, mixing phenylboronic acid (16) with 28 gave the
expected product 29 in high yield. These results suggest that
the real aminating agent of our reaction could be 28.[17] We
further prepared a monodeuterated compound 30-d1 and
subjected it to our standard reaction conditions (Scheme 2b).
We isolated 31-d1 after protection of the resulting amine with
a tosyl group. We found that the deuterium atom in 31-d1 is
positioned cis relative to the amide group, suggesting that the
amination of 30-d1 proceeds with stereoretention. Based on
this information, we surmise that our reaction proceeds via
a transition-state structure such as 32, in which the migration
of the R1 group from the B to the N atom results in the
expulsion of the trichloroimidate group (Scheme 2c). We
propose that the relaxation of the imidate in 32 to an amide
group contributes to the lowering of the activation energy of
this process.
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
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In conclusion, we have developed a mild method for the
amination of organoboronic acids with N-alkyl hydroxyl-
amines in the presence of trichloroacetonitrile. Salient
features of this reaction include that 1) it converts organo-
boronic acids into the corresponding secondary amines in the
absence of added metal or base, 2) it employs readily
available starting materials, 3) it is operationally simple,
occurs rapidly at room temperature, and can be performed
open to air, and 4) it tolerates a broad scope of functional
groups, and can be used in the late-stage coupling of two
complex substrates. Experimental studies provided insight
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Acknowledgements
Funding from the National Natural Science Foundation
(21602145 and 21772125), the 1000 Talent plan program,
and start-up funding from Sichuan University is acknowl-
edged.
Conflict of interest
The authors declare no conflict of interest.
Keywords: amination · amines · boronic acids · hydroxylamines ·
trichloroacetonitrile
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[17] The yield of this reaction is not affected by the order of reagent
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[9] a) H. C. Brown, G. W. Kramer, A. B. Levy, M. M. Midland,
Organic Syntheses via Boranes, Wiley-Interscience, New York,
1975; b) H. C. Brown, A. M. Salunkhe, A. B. Argade, Organo-
metallics 1992, 11, 3094 – 3097; c) O. Phanstiel IV. , Q. X. Wang,
D. H. Powell, M. P. Ospina, B. A. Leeson, J. Org. Chem. 1999, 64,
803 – 806; d) E. Hupe, I. Marek, P. Knochel, Org. Lett. 2002, 4,
2861 – 2863; e) D. S. Matteson, G. Y. Kim, Org. Lett. 2002, 4,
2153 – 2155; f) B. J. Kim, D. S. Matteson, Angew. Chem. Int. Ed.
2004, 43, 3056 – 3058; Angew. Chem. 2004, 116, 3118 – 3120; g) V.
Bagutski, T. G. Elford, V. K. Aggarwal, Angew. Chem. Int. Ed.
2011, 50, 1080 – 1083; Angew. Chem. 2011, 123, 1112 – 1115.
[10] The conversion of acyl trifluoroborates into amides has been
reported and applied in the synthesis/derivatization of complex
peptides and proteins; for examples, see: a) A. M. Dumas, G. A.
Molander, J. W. Bode, Angew. Chem. Int. Ed. 2012, 51, 5683 –
Manuscript received: March 6, 2018
Version of record online: && &&, &&&&
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Hydroxylamines
The amination of organoboronic acids
was achieved through the use of N-alkyl
hydroxylamines in the presence of tri-
chloroacetonitrile but in the absence of
added metal or base. This reaction fea-
tures a remarkably broad substrate scope
and can be applied to the late-stage
coupling of two complex units.
H.-B. Sun, L. Gong, Y.-B. Tian, J.-G. Wu,
X. Zhang, J. Liu, Z. Fu,
D. Niu*
&&&& — &&&&
Metal- and Base-Free Room-Temperature
Amination of Organoboronic Acids with
N-Alkyl Hydroxylamines
6
www.angewandte.org
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
These are not the final page numbers!